This invention relates to methods and therapeutic compositions for the treatment or prevention of central nervous system (CNS) cell damage in mammalsxe2x80x94also peripheral nervous system protectionxe2x80x94and more particularly relates to a method of increasing the concentration of specified naturally occurring or introduced 2- or 3-peptides within the central nervous system to treat an injury or disease affecting or liable to affect cells of the CNS (or PNS).
The central nervous system is peculiar among mammalian organs in that differentiated neurones are practically incapable of regeneration. Permanent loss of function is a likely outcome of a sufficiently severe injury to the brain. It is particularly sad to meet children whose brains have been damaged by hypoxia during a difficult birth. There is therefore a need for means to protect cells of the central nervous system (also including the glial cells) from death after an injury.
After asphyxial, traumatic, toxic, infectious, degenerative, metabolic, ischaemic or hypoxic insults to the central nervous system (CNS) of man or other mammals a certain degree of damage in several different cell types may result. For example periventricular leucomalacia, a lesion which affects the periventricular oligodendrocytes is generally considered to be a consequence of hypoxic ischemic injury to the developing preterm brain (Bejar et al., Am. J. Obstet. Gynecol., 159:357-363 (1988); Sinha et al., Arch. Dis. Child., 65:1017-1020 (1990); Young et al., Ann. Neurol., 12:445-448 (1982)). Damage to the CNS by trauma, asphyxia, ischemia, toxins or infection is frequent and may cause sensory, motor or cognitive deficits. Glial cells which are non-neuronal cells in the CNS are necessary for normal CNS function. Infarcts are a principal component of some hypoxic ischemic induced damage and loss of glial cells is an essential component of infarction. There appears to be a kind of xe2x80x9cdelayed injury processxe2x80x9d in which apparently xe2x80x9cself-destructivexe2x80x9d neural activity occurs some time after an injury; attempts to control this activity appear able to alleviate the effects of this delayed injury process.
Diseases of the CNS also may cause loss of specific populations of cells. For example multiple sclerosis is associated with loss of myelin and oligodendrocytes, similarly Parkinson""s disease is associated with loss of dopaminergic neurons. Some situations in which CNS injury or disease can lead to predominant loss of neurons and/or other cell types include: perinatal asphyxia associated with fetal distress such as following abruption, cord occlusion or associated with intrauterine growth retardation; perinatal asphyxia associated with failure of adequate resuscitation or respiration; severe CNS insults associated with near-miss drowning, near-miss cot death, carbon monoxide inhalation, ammonia or other gaseous intoxication, cardiac arrest, collapse, coma, meningitis, hypoglycaemia and status epilepticus; episodes of cerebral asphyxia associated with coronary bypass surgery; cerebral anoxia or ischemia associated with stroke, hypotensive episodes and hypertensive crises; and cerebral trauma.
There are many other instances in which CNS injury or disease can cause damage to cells of the CNS. It is desirable to treat the injury in these instances. Also, it is desirable to prevent or reduce the amount of CNS damage which may be suffered as a result of induced cerebral asphyxia in situations such as cardiac bypass surgery.
We have previously shown (in New Zealand Patent Application No. 239211- xe2x80x9cIGF-1 to improve neural outcomexe2x80x9d, the contents of which are hereby incorporated by way of reference) that the growth factor called insulin-like growth factor 1 (IGF-1) has an unanticipated action, namely to prevent brain cells from dying after an asphyxial or ischemic brain insult (Gluckman et al Biochem Biophys Res Commun 182:593-599 1992). Because insulin also has a neuroprotective action (Voll et al Neurology 41:423-428 (1991)) and insulin and IGF-1 can both bind to the IGF-1 receptor, it was generally assumed that this brain rescue mode of action of IGF-1 was mediated via the IGF-1 receptor (Guan et al J. Cereb. Blood Flow Metab. 13:609-616 (1993)).
It is known that IGF-1 can be modified by proteolytic cleavage in nervous tissue to des 1-3N IGF-1, that is IGF-1 missing the 3 amino acids from the amino terminal of the molecule, and hence after cleavage there is also a 3 amino acid peptide gly-pro-glu which is the N terminal tripeptide. This tripeptide is also termed GPE. As des 1-3N IGF-1 also binds to the IGF-1 receptor and GPE does not, the GPE was thought to be of no significance to the neuronal rescue action of IGF-1.
Our previous work had shown that the brain increases its production of IGF-1 following brain injury by hypoxia-ischemia and that in addition it increases the synthesis of two specific binding proteins, IGF binding protein-2 (IGFBP-2) and IGF binding protein-3 (IGFBP-3) (Gluckman et al Biochem Biophys Res Commun 182:593-599 1992) and Klemp et al Brain Res 18:55-61 (1992). These were hypothesised to attract the IGF-1 into the region of injury to reach concentrations necessary for neuronal rescue. For this reason IGF-1 was anticipated to be more potent given at a site distant from the injury than des 1-3 N IGF-1 which does not bind well to the binding proteins. This was indeed the casexe2x80x94des 1-3 N IGF-1 was not significantly active as a neuronal rescue agent at a dose equivalent to that at which IGF-1 shows neuronal rescue activity. Thus the prior art pointed to activity at the IGF-1 receptor as the mode of neuronal rescue achieved with IGF-1.
To date, there has been no enabling reference in the prior art to the manipulation of the cleaved tripeptide GPE itself to prevent or treat CNS injury or disease leading to CNS damage in vivo.
It is an object of the invention to provide a method and/or medicament (therapeutic composition) for treating or preventing CNS damage which will go at least some way to meeting the foregoing desiderata in a simple yet effective manner or which will at least provide the public with a useful choice.
Accordingly, in a broad aspect the invention comprises a method of treating neural damage suffered by mammals (or patients) including the step of increasing the active concentration of the tripeptide GPE (the 3 amino acid peptide gly-pro-glu) and/or the concentration of analogues of GPE in the CNS of the mammal. In particular, the concentration of GPE in the CNS of the mammal is effectively increased.
Among preferred analogues of GPE are peptides selected from the group; gly pro glu (GPE), gly pro, and pro glu.
In a related aspect the invention relates to treatment for injury to the central nervous system (CNS) which is taken for the purpose of possible loci of activity of GPE to include those parts of the nervous system where cell bodies (including neurones and supporting cells such as glia, Schwann cells or the like) are located. Thus treatment of the peripheral nerves is a part of the invention as well as treatment of the brain, spinal cord, and the like.
More particularly the invention comprises a method for treating neuronal injury within at least the hippocampus.
(The term xe2x80x9ctreatxe2x80x9d when used herein refers to at least attempting to effect a reduction in the severity of the CNS damage, by reducing neuronal loss, and loss of glial cells and other cells, suffered after a CNS injury. It encompasses the minimising of such damage following a CNS injury.)
(The term xe2x80x9cinjuryxe2x80x9d when used herein encompasses asphyxia, ischemia, stroke, toxins, infections, trauma, haemorrhage, and surgical damage to the CNS.)
Preferably, GPE and/or analogues thereof are administered to the patient directly. Alternatively, a compound may be administered which upon administration to the patient increases the active concentration of GPE or naturally occurring analogues of GPE in the CNS of the patient. For example, increasing the availability of IGF-1 may lead to increased concentrations of GPE.
Preferably, the medicament is administered in the period from before the time of injury and/or up to 100 hours after the CNS injury and more preferably 0.5 to 8 hours after the CNS injury.
Alternatively if an elective procedure is considered likely to lead to an injury to the CNS the medicament may be administered prior to the elective procedure, thereby arranging for raised levels of GPE during the procedure.
In a first form, preferably, said GPE and/or an analogue or analogues thereof selected from the group; gly pro glu, gly pro, pro glu, is administered by lateral cerebro-ventricular injection or through a surgically inserted shunt into the lateral cerebro ventricle of the brain of a patient in the inclusive period from the time of the CNS injury to 8 hours thereafter.
In another preferred form, GPE and/or an analogue or analogues thereof selected from the group; gly pro glu, gly pro, pro glu, is administered by injection into the cerebral parenchyma of a patient in the inclusive period from the time of the CNS injury to 8 hours thereafter.
In another preferred form of the present invention, GPE and/or an analogue or analogues thereof selected from the group; gly pro glu, gly pro, pro glu, is administered peripherally into a patient for passage into the lateral ventricle of the brain in the inclusive period of from the time of the CNS injury to 8 hours thereafter. By peripheral route, we mean an intravenous, oral, rectal, nasal, subcutaneous, inhalation, intraperitoneal or intramuscular route. Preferably, it is GPE itself that is administered by way of lateral cerebro ventricle injection or by use of the surgically inserted shunt.
Preferably the medicament is administered according to the pattern of injury or time lapsed after a CNS injury.
Preferably the dosage range administered is from about 0.1 xcexcg to about 10 mg of GPE (or said analogue or said compound that elevates the concentration thereof) per 100 gm of body weight.
More preferably the dosage range administered is about 1 mg of GPE per 100 gm of body weight.
Optionally the dose rate may be about 10 xcexcg/kg for infusion, in artificial CSF, into the lateral ventricle or other perfusion sites suitable for access to the CSF.
GPE (or said analogue or said compound that elevates the concentration thereof) may be used alone or in conjunction with other medicaments or growth factors designed to ameliorate against loss of CNS cells such as glia and neurons.
By xe2x80x9cpreventxe2x80x9d is meant a reduction in the severity of CNS damage suffered after a CNS injury and may consequently include inhibition of the symptoms of CNS damage.
In yet a further aspect, the invention provides the use of GPE and/or analogues thereof in the preparation of a medicament for treating CNS damage.
Alternatively, the invention comprises the use of a compound which, upon administration to a patient, increases the active concentration of GPE and/or naturally occurring analogues thereof in the CNS of the patient in the preparation of a medicament for treating injury to the CNS.
The invention also consists in a medicament suitable for treating CNS damage suffered after a CNS injury comprising GPE, and/or analogues thereof optionally provided in human dosage form in a pharmaceutically acceptable carrier or diluent.
In a related aspect the medicament comprising GPE may be provided together with suitable pharmaceutically acceptable excipients.
In a further related aspect the medicament comprising GPE may be provided in a manunalian dosage form.
In another related aspect the medicament for treating CNS damage may also comprise a compound or composition in human dosage form which, upon administration to the patient suffering CNS damage, increases the active concentration of GPE and/or naturally occurring analogues thereof in the CNS of said patient.
Alternatively the medicament stimulating GPE levels may be provided in a mammalian dosage form.
The invention further provides a method of treating patients suffering chronic forms of degeneration of the nervous system by administering GPE and/or analogues thereof over an extended period.
Preferably GPE, and/or analogues thereof (optionally with suitable pharmaceutically acceptable carriers or the like) may be administered to such patients in a form and by a route in which absorbtion takes place across mucous membranes.
Optionally GPE, and/or analogues thereof may be provided as molecules having an electric charge and absorbtion may be aided by an electrophoretic procedure.
Optionally, the invention further provides for the prophylactic use of a substance (GPE or an analogue or a compound that elevates the concentration thereof) to minimise the effects of CNS damage during anticipated events, for example certain procedures such as open-heart surgery)
Although the present invention is defined broadly above, it will be appreciated by those skilled in the art that it is not limited thereto but includes embodiments of which the description provides examples.